Symptomatic care of late-onset Alexander disease presenting with area postrema-like syndrome with prednisolone; a case report.

BACKGROUND: Alexander disease (AxD) is classified into AxD type I (infantile) and AxD type II (juvenile and adult form). We aimed to determine the potential genetic cause(s) contributing to the AxD type II manifestations in a 9-year-old male who presented area postrema-like syndrome and his vomiting and weight loss improved after taking prednisolone. CASE PRESENTATION: A normal cognitive 9-year-old boy with persistent nausea, vomiting, and a significant weight loss at the age of 6 years was noticed. He also experienced an episode of status epilepticus with generalized atonic seizures. He showed non-febrile infrequent multifocal motor seizures at the age of 40 days which were treated with phenobarbital. He exhibited normal physical growth and neurologic developmental milestones by the age of six. Occasionally vomiting unrelated to feeding was reported. Upon examination at 9 years, a weak gag reflex, prominent drooling, exaggerated knee-deep tendon reflexes (3+), and nasal tone speech was detected. All gastroenterological, biochemical, and metabolic assessments were normal. Brain magnetic resonance imaging (MRI) revealed bifrontal confluent deep and periventricular white matter signal changes, fine symmetric frontal white matter and bilateral caudate nucleus involvements with garland changes, and a hyperintense tumefactive-like lesion in the brain stem around the floor of the fourth ventricle and area postrema with contrast uptake in post-contrast T1-W images. Latter MRI at the age of 8 years showed enlarged area postrema lesion and bilateral middle cerebellar peduncles and dentate nuclei involvements. Due to clinical and genetic heterogeneities, whole-exome sequencing was performed and the candidate variant was confirmed by Sanger sequencing. A de novo heterozygous mutation, NM_001242376.1:c.262 C > T;R88C in exon 1 of the GFAP (OMIM: 137,780) was verified. Because of persistent vomiting and weight loss of 6.0 kg, prednisolone was prescribed which brought about ceasing vomiting and led to weight gaining of 3.0 kg over the next 3 months after treatment. Occasional attempts to discontinue prednisolone had been resulting in the reappearance of vomiting. CONCLUSIONS: This study broadens the spectrum of symptomatic treatment in leukodystrophies and also shows that R88C mutation may lead to a broad range of phenotypes in AxD type II patients.

CEP104 gene may involve in the pathogenesis of a new developmental disorder other than joubert syndrome.

BACKGROUND: The CEP104 gene (OMIM: 616,690) encodes the centrosome protein 104 (CEP104) that is involved in cilia function. Pathogenic variants in this gene have been described in four patients diagnosed with Joubert syndrome (JBTS) 25. Here, we challenged the concept that pathogenic variants in CEP104 gene are only involved in the development of JBTS 25. METHODS AND RESULTS: In a clinical setting, whole-exome sequencing (WES) was applied to investigate pathogenic variants in patients with unexplained developmental delay or intellectual disability (DD/ID).WES revealed a novel homozygous nonsense variant (c.643C > T) in CEP104 (NM _014704.3) in a girl with mild intellectual disability, hypotonia, and imbalanced gait. Her brain MRI data did not show molar tooth sign (MTS) or any other brain anomalies. CONCLUSION: Our study introduced a novel variant in the CEP104 gene that results in an ID phenotype other than JBTS25. Comparison of her phenotype with that of eight previously published DD/ID patients harboring pathogenic variants in CEP104 gene revealed that more than half of them did not show JBTS related symptoms. Therefore, we suggest that the CEP104 gene might also be involved in a disorder other than JBTS 25, a point that deserves to be emerged in the OMIM database.

Primary and Secondary Microcephaly, Global Developmental Delay, and Seizure in Two Siblings Caused by a Novel Missense Variant in the ZNF335 Gene.

Autosomal recessive microcephaly is a rare clinical condition, which is characterized by reduced brain size that can be associated with delayed intellectual ability, developmental delay, and seizure. In this study, we describe two siblings with microcephaly: a 12-year-old girl with primary microcephaly, and a 7-year-old boy with secondary microcephaly, whose episodes of seizure and neurodevelopmental regression started at 6 years and 6 months of age, respectively. The interesting finding in these siblings was two different presentations of the same variant: one case with primary and one case with secondary microcephaly. Whole-exome sequencing was performed in order to identify causative variants in one family having two affected siblings with microcephaly. Confirmation of the identified variant in the ZNF335 gene in the proband and her affected brother and segregation analysis in the family were performed using the Sanger sequencing method. In both patients, a novel homozygous missense variant, [NM_022095.4: c.3346G>A; p.(Gly1116Arg)], in the ZNF335 gene was identified. The p.(Gly1116Arg) variant causes a defect in the last zinc finger domain of the protein. Conservation analysis by ConSurf server and UCSC genome browser revealed that Gly1116 is a highly conserved amino acid among different species. Different in-silico prediction tools and bioinformatics analysis predicted this variant as damaging.

Defective complex III mitochondrial respiratory chain due to a novel variant in CYC1 gene masquerades acute demyelinating syndrome or Leber hereditary optic neuropathy.

Complex III (CIII) is the third out of five mitochondrial respiratory chain complexes residing at the mitochondrial inner membrane. The assembly of 10 subunits encoded by nuclear DNA and one by mitochondrial DNA result in the functional CIII which transfers electrons from ubiquinol to cytochrome c. Deficiencies of CIII are among the least investigated mitochondrial disorders and thus clinical spectrum of patients with mutations in CIII is not well defined. We report on a 10-year-old girl born to consanguineous Iranian parents presenting with recurrent visual loss episodes and optic nerve contrast enhancement in brain imaging reminiscent of an acquired demyelination syndrome (i.e. optic neuritis or multiple sclerosis), who was ultimately confirmed to have a novel homozygous missense variant of unknown significance, c.949C > T; p.(Arg317Trp) in the CYC1 gene, a nuclear DNA subunit of complex III of the mitochondrial chain. Sanger sequencing confirmed the segregation of this variant with disease in the family. The effect of this variant on the protein structure was shown in-silico. Our findings, not only expand the clinical spectrum due to defects in CYC1 gene but also highlight that mitochondrial respiratory chain disorders could be considered as a potential differential diagnosis in children who present with unusual patterns of acquired demyelination syndromes (ADS). In addition, our results support the hypothesis that mitochondrial disorders might have an overlapping presentation with ADS.

Leukoencephalopathy in Al-Raqad syndrome: Expanding the clinical and neuroimaging features caused by a biallelic novel missense variant in DCPS.

Al-Raqad syndrome (ARS) is a rare autosomal recessive congenital disorder, associated mainly with developmental delay, and intellectual disability. This syndrome is caused by mutations in DCPS, encoding scavenger mRNA decapping enzyme, which plays a role in the 3-prime-end mRNA decay pathway. Whole-exome sequencing was performed on an offspring of a consanguineous family presenting with developmental delay, intellectual disability, growth retardation, mild craniofacial abnormalities, cerebral and cerebellar atrophy, and white matter diffuse hypomyelination pattern. A novel biallelic missense variant, c.918G>C p. (Glu306Asp), in the DCPS gene was identified which was confirmed by sanger sequencing and segregation analysis subsequently. Few cases of ARS have been described up to now, and this study represents a 7-years-old boy presenting with central and peripheral nervous system impaired myelination in addition to ocular and dental manifestation, therefore outstretch both neuroimaging and clinical findings of this ultra-rare syndrome.

Expanding the clinical and neuroimaging features of NKX6-2-related hereditary spastic ataxia type 8.

Pathogenic variants in NKX6-2 gene causing autosomal recessive spastic ataxia type 8 with hypomyelinating leukodystrophy have been reported in few families around the world. In this study, we performed Whole Exome Sequencing and identified a novel missense variant, c.501C > G; p.(Phe167Leu), in two affected siblings with main manifestations of global developmental delay, motor regression, hypotonia, clonus in lower limbs and muscle bulk atrophy especially in the upper limbs, spasticity and contracture, scoliosis, hip dislocation, oculomotor apraxia, horizontal and vertical nystagmus. In addition, wrist and foot drop due to peripheral axonal neuropathy were observed in these patients as a new clinical finding and cerebellar white matter involvement in brain Magnetic Resonance Imaging (MRI) as new imaging finding. Therefore, we expanded the manifestations of NKX6-2-related disorders in this manuscript.